Determination of smoothness of canisters containing inhalable medicaments

ABSTRACT

Disclosed are methods for determining the smoothness index of the interior of a metered dose container.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims benefit of priority to U.S. ProvisionalPatent Application 60/403,941, filed Aug. 16, 2002.

BACKGROUND OF THE INVENTION

[0002] The present invention pertains to aerosol formulations of drugs,such as those formulations suitable for use in pressurized aerosolmetered dose inhalers.

[0003] Aerosolized drugs have been used for many years to treatdisorders of the respiratory system, and as a convenient means for thesystemic introduction of various pharmaceutical agents into the body.The typical aerosol formulation in a metered dose inhaler for treatingdisorders such as asthma or rhinitis is a suspension of one or more drugsubstances in a fully halogenated (with chlorine and/or fluorine) loweralkyl compound propellant, further containing small amounts ofsurfactants and/or excipients which are usually soluble in thepropellant. Pharmaceutical agents administered by means of metered doseinhalers are usually bronchodilators or corticosteroids.

[0004] Typical formulations contain chlorofluorocarbon propellants, thedrug substance and ethanol, which is miscible with the propellant, andsometimes also contain a surfactant such as oleic acid for maintaining astable suspension, lubrication of the metering valve and otherfunctions.

[0005] In general, drug particle sizes from about 1 to about 5 μm arepreferred for administration to the lower airway, with particles smallerthan about 0.5 μm frequently being exhaled without complete depositionon tissues, while particles larger than about 10 μm can exhibitconsiderable deposition in the mouth and/or pharynx and therefore notreach the lower airway. Very large particles cannot pass through ametering valve and will not be reliably dispensed.

[0006] With the implication of fully halogenated chlorofluorocarbonpropellants in the environmentally harmful destruction of ozone in theupper atmosphere, the availability of these propellants has become quiterestricted. This has encouraged development work toward formulationscontaining propellants having reduced upper atmospheric reactivity, suchwork particularly centering about the propellants HFC 134a and HFC 227,these compounds having approximately the same physical properties asthose of the older chlorofluorocarbons used for medicinal aerosols.

[0007] Metered dose inhalers typically employ metallic canisters tostore the medicament, propellant and excipients. The inner wall of thecanister can, for example, be embedded with various plastic coatings,e.g. Teflon. This aids in preventing deposition of the medicament on tothe wall.

[0008] It is preferable that the inside of the container or can that isin contact with the medicament be as smooth possible. This is so becauseirregularities in the surface of the container can provide a seed areafor the medicament to first lodge or deposit and eventually grow. Theprocess of mass transfer and consequent deposition of the medicamentcrystals is usually dependent on the crystal size of the medicament, thepresence of impurities, and the temperature of the ambient and surfaceirregularities.

[0009] These surface irregularities may provide a locus for thedeposition of larger crystals which have higher settling velocities.These would create a “mass transfer” boundary layer where mass transferproceeds by molecular diffusion. Fluctuations in the ambienttemperature, as encountered during shipping and handling, can lead tocrystal growth, the activation energy for which is temperature dependentand follows the Arrhenius equation. These “growing” crystals would alsoremain lodged/deposited on the surface imperfection and thus becomeunavailable for delivery. Therefore overtime, this phenomenon of canwall deposition can lead to a decrease in the amount of medicament thatis dispensed to the patient.

[0010] There thus exists a need for dosing systems having canisters withsmooth interiors that minimize the possibility of can wall deposition bynot providing the locii for crystal deposition such that it is ensuredthat the patient receives the requisite amount of medication.

SUMMARY OF THE INVENTION

[0011] Accordingly, there is disclosed a method for determining asmoothness index of a metered dose container having an inner corecomprising the steps of subjecting said inner core of said metered dosecontainer to reflected light photomicrography to obtain a digital imagecontaining a plurality of pixels of said inner core, determining fromsaid digital image the brightness of each of said pixels and quantifyingsaid brightness by assigning an integer value thereto, wherein saidvalue corresponds to an amount of brightness and comparing saidbrightness of said pixel to a reference standard to determine thesmoothness index of said inner core of said metered dose container.

[0012] There is also disclosed a method for determining a smoothnessindex of a metered dose container having an inner core comprising thesteps of subjecting said inner core of said metered dose containercontaining at least one pharmacologically active agent to reflectedlight photomicrography to obtain a digital image containing a pluralityof pixels of said inner core, determining from said digital image thebrightness of each of said pixels and quantifying said brightness byassigning an integer value thereto, wherein said value corresponds to anamount of brightness and comparing said brightness of said pixel to areference standard to determine the smoothness index of said inner coreof said metered dose container.

BRIEF DESCRIPTION OF THE DIGITAL MICROGRAPHS

[0013] Digital Micrograph 1 is of an epoxy coated can withimperfections.

[0014] Digital Micrograph 2 is of an FEP coated can.

[0015] Digital Micrograph is of a 3 PFA coated can with non-optimizedcoating.

[0016] Digital Micrograph 4 is of a PFA coated can with optimizedcoating.

[0017] Digital Micrograph 5 is of an Epoxy coated can with drug.

DETAILED DESCRIPTION OF THE INVENTION

[0018] Accordingly, there is disclosed the use of reflected lightphotomicrography and digital image analysis as a quantitative andqualitative measure of the surface smoothness of coated and uncoatedcans used for the packaging of pressurized aerosols.

[0019] A qualitative and quantitative physical description of surface'ssmoothness is defined in this invention as a Smoothness Index. Thepresent invention is based upon the use of reflected light in amicroscope to obtain a digital image and process this image utilizingimage processing. Image processing manipulates information within animage to make it more useful; digital image processing is a specifictype of image processing performed with a computer.

[0020] The image is thereafter digitized whereby the image is dividedinto a horizontal grid, or array, of very small regions called pixels(picture elements). In the computer the image is represented by thisdigital grid, or bitmap. Each pixel in the bitmap is identified by itsposition in the grid, as referenced by its row (x) number and column (y)number. When a source image, such as a photograph, is digitized, it isexamined in grid fashion. That is, each pixel in the image isindividually sampled, and it brightness is measured and quantified.

[0021] This measurement results in a value for the pixel, usually aninteger, which represents the brightness or darkness of the image atthat point. This value is stored in the corresponding pixel of thecomputer's image bit map. It is these areas of brightness and darknessthat were used for the qualitative and quantitative evaluation of theamount of light reflected off the studied surfaces, and hence theirsmoothness. The brighter the area in the image, the more light isreflected, and therefore, the smoother it is; the darker the area in theimage is, the less light is reflected, and therefore, the less smooth itis. The integers, obtained for the studied surfaces, representing theamount of reflected light are compared to the integer obtained fromaluminum foil, used as a standard reference material for reflection oflight.

[0022] The ratio of the integer for the studied surface to the integerobtained for the aluminum foil was called the “Smoothness Index,” thecloser the ratio to one the brighter, and hence, the smoother thesurface is. The smoothness index is defined as follows:

Smoothness Index=Amount of Reflected Light from the StudiedSurface÷Amount of Light Reflected from Aluminum Foil Standard

[0023] Advantages of the present invention included the ability todistinguish between cans used for MDI products, with various surfacesmoothness, i.e., possible imperfection in the surface of cans coatedwith the same material, e.g., epoxy coated cans. See DigitalMicrograph 1. Another feature of the invention is to distinguish betweencans coated with various materials, e.g., epoxy coated versus tefloncoated. See Digital Micrographs 1 and 2. Another advantage of theinvention is to distinguish between cans coated with the same materialsuch as teflon, but cured at different conditions. See DigitalMicrographs 3 and 4. Another advantage of the invention is to detectdrug deposition on the surface of these cans. See Digital Micrograph 5.

[0024] The canisters of the present invention can have an inner corethat is preferably embedded with various forms of Teflon. As usedherein, Teflon PTFE is defined as polytetrafluoroethylene; Teflon FEP isdefined as fluorinated ethylene copolymer; Teflon PFA is defined asperfluoroalkoxy ethylene propylene copolymer; and Teflon ETFE is definedas a copolymer of ethylene and tetrafluoroethylene. The inner core mayalso be embedded or treated with other coatings and/or materials such aslacquer, epoxy resin and other materials as known to one of the art.

[0025] Preferably, the method in accordance with the present inventionanalyzes dosing systems that employ a canister containing at least onepharmacologically active agent or drug that is a material capable ofbeing administered to the respiratory system, including the lungs. Forexample, a drug in accordance with the present invention could beadministered so that it is absorbed into the blood stream through thelungs. Particularly preferred pharmacologically active agents inaccordance with the present invention include, without limitation,corticosteroids such as: mometasone furoate anhydrous; beclomethasonedipropionate; budesonide; fluticasone; dexamethasone; flunisolide;triamcinolone;(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione;tipredane and the like. Mometasone furoate anhydrous is the mostpreferred and is available from Schering-Plough Corporation.

[0026] β-agonists (including β₁ and β₂-agonists) including, withoutlimitation, albuterol, terbutaline, salmeterol, and bitolterol may alsobe administered with the present invention. Formoterol (also known aseFormoterol) e.g., as the fumarate or tartrate, a highly selectivelong-lasting β₂-adrenergic agonist having bronchospasmolytic effect, iseffective in the treatment of reversible obstructive lung ailments ofvarious genesis, particularly asthmatic conditions and may also beadministered with the present invention. Another long-acting β-agonistwhich can be administered in accordance with the present invention isknown as TA-2005, chemically identified as 2(1H)-Quinolinone,8-hydroxy-5-[1-hydroxy-2-[[2-(4-(methoxyphenyl)-1-methylethyl]amino]ethyl]-monohydrochloride,[R—(R*,R*)]—.

[0027] Anticholinergics such as ipratropium bromide and oxitropiumbromide may be used in the present invention. So, too can sodiumcromoglycate, nedocromil sodium and leukotriene antagonists such asmontelukast, zafirlukast and pranlukast. Bambuterol (e.g. ashydrochloride), fenoterol (e.g. hydrobromide), clenbuterol (e.g. ashydrochloride), procaterol (e.g. as hydrochloride), and broxaterol arehighly selective β₂-adrenergic agonists can be administered.

[0028] Several of these compounds could be administered in the form ofpharmacologically acceptable esters, salts, solvates, such as hydrates,or solvates of such esters or salts, if any. The term is also meant tocover both racemic mixtures as well as one or more optical isomers.

[0029] The canister containing a drug in accordance with the presentinvention can also be an inhalable protein or a peptide such as insulin,interferons, calcitonins, parathyroid hormones, granulocytecolony-stimulating factor and the like. “At least one pharmacologicallyactive agent” as used herein may refer to a single pharmacologicallyactive entity, or to combinations of any two or more, an example of auseful combination being a dosage form including both a corticosteroidand a β-agonist.

[0030] Also within the scope of the present invention are the analysisof canisters containing combinations of any of the above pharmaceuticalproducts, e.g. a corticosteroid may be combined with a β-agonist in asingle formulation. One such preferred combination is that of mometasonefuroate anhydrous with formoterol fumarate.

[0031] The amount of drug administered will vary with a number offactors including, without limitation, the age, sex, weight, conditionof the patient, the drug, the course of treatment, the number of dosesper day and the like. For example, for mometasone furoate anhydrous, theamount of drug delivered per dose, i.e. per inhalation, will generallyrange from about 10 μg to about 10,000 μg. Doses of 25 μg, 50 μg, 75 μg,100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 250 μg, 300 μg, 400 μg and/or500 μg are preferred.

[0032] To be topically effective in the lungs or the upper and/or lowerairway passages, it is important that the pharmacologically active agentbe delivered as particles of about 10 μm or less. The ability of adosage form to actually administer free particles of thesetherapeutically effectively sized particles is the fine particlefraction. Fine particle fraction is, therefore, a measure of thepercentage of bound drug particles released as free particles of drughaving a particle size below some threshold during administration. Fineparticle fraction can be measured using a multi-stage liquid impingermanufactured by Copley Instruments (Nottingham) LTD using themanufacturer's protocols. In accordance with the present invention, anacceptable fine particle fraction is at least 10% by weight of the drugbeing made available as free particles having an aerodynamic particlesize of 6.8 μm, or less, measured at a flow rate of 60 liters perminute.

[0033] Propellant-based pharmaceutical aerosol formulations in the artuse a mixture of liquid chlorofluorocarbons as the propellant.Fluorotrichloromethane, dichlorodifluoromethane anddichlorotetrafluoroethane are the most commonly used propellants inaerosol formulations for administration by inhalation. Suchchlorofluorocarbons (CFCs), however, have been implicated in thedestruction of the ozone layer and their production is being phased out.Hydrofluorocarbon 134a, also known as 1,1,1,2-tetrafluoroethane or HFC134a, and hydrofluorocarbon 227a, also known as1,1,1,2,3,3,3-heptafluoropropane or HFC 227, are said to be less harmfulto the ozone than many chlorofluorocarbon propellants, and both ormixtures thereof are considered to be used within the scope of thepresent invention.

[0034] The formulations of the present invention may be filled into theaerosol containers using conventional filling equipment. Sincepropellants 227 and 134 may not be compatible with all elastomericcompounds currently utilized in present aerosol valve assemblies, it maybe necessary to substitute other materials, such as white buna rubber,or to utilize excipients and optionally surfactants which mitigate theadverse effects of propellant 227 or 134 on the valve components.

[0035] The excipient facilitates the compatibility of the medicamentwith the propellant and also lowers the discharge pressure to anacceptable range, i.e., about 2.76-5.52×10⁵ newton/meter² absolute (40to 80 psi), preferably 3.45-4.83×10⁵ newton/meter² absolute (50 to 70psi). The excipient chosen must be non-reactive with the medicaments,relatively non-toxic, and should have a vapor pressure below about3.45×10⁵ newton/meter² absolute (50 psi).

[0036] As used hereinafter the term “medium chain fatty acids” refers tochains of alkyl groups terminating in a —COOH group and having 6-12carbon atoms, preferably 8-10 carbon atoms. The term “short chain fattyacids” refers to chains of alkyl groups terminating in a —COOH group andhaving 4-8 carbon atoms. The term “alcohol” includes C₁-C₃ alcohols,such as methanol, ethanol and isopropanol.

[0037] Among the preferred excipients are: propylene glycol diesters ofmedium chain fatty acids available under the tradename Miglyol 840 (fromHuls America, Inc. Piscataway, N.J.); triglyceride esters of mediumchain fatty adds available under the tradename Miglyol 812 (from Huls);perfluorodimethylcyclobutane available under the tradename Vertrel 245(from E. I. DuPont de Nemours and Co. Inc. Wilmington, Del.);perfluorocyclobutane available under the tradename octafluorocyclobutane(from PCR Gainsville, Fla.); polyethylene glycol available under thetradename EG 400 (from BASF Parsippany, N.J.); menthol (fromPluess-Stauffer International Stanford, Conn.); propylene glycolmonolaurate available under the tradename lauroglycol (from GattefosseElmsford, N.Y.); diethylene glycol monoethylether available under thetradename Transcutol (from Gattefosse); polyglycolized glyceride ofmedium chain fatty adds available under the tradename Labrafac Hydro WL1219 (from Gattefosse); alcohols, such as ethanol, methanol andisopropanol; eucalyptus oil available (from Pluses-StaufferInternational); and mixtures thereof.

[0038] A surfactant is frequently included in aerosol formulations, forpurposes such as assisting with maintaining a stable suspension of thedrug and lubricating the metering valve. The formulation of the presentinvention does not require a surfactant for maintenance of readydispersability (such as by moderate agitation immediately prior to use),as the drug forms loose flocculates in the propellant and does notexhibit a tendency to settle or compact. Upon undisturbed storage, thedrug particles remain suspended in their flocculated state. Among thepreferred surfactants are: oleic acid available under the tradenameoleic acid NF6321 (from Henkel Corp. Emery Group, Cincinnati, Ohio);cetylpyridinium chloride (from Arrow Chemical, Inc. Westwood, N.J.);soya lecithin available under the tradename Epikuron 200 (from LucasMeyer Decatur, Ill.); polyoxyethylene(20) sorbitan monolaurate availableunder the tradename Tween 20 (from ICI Specialty Chemicals, Wilmington,Del.); polyoxyethylene(20) sorbitan monostearate available under thetradename Tween 60 (from ICI); polyoxyethylene(20) sorbitan monooleateavailable under the tradename Tween 80 (from ICI); polyoxyethylene (10)stearyl ether available under the tradename Brij 76 (from ICI);polyoxyethylene (2) oleyl ether available under the tradename Brij 92(frown ICI); Polyoxyethylene-polyoxypropylene-ethylenediamine blockcopolymer available under the tradename Tetronic 150 R1 (from BASF);polyoxypropylene-polyoxyethylene block copolymers available under thetradenames Pluronic L-92, Pluronic L-121 end Pluronic F 68 (from BASF);castor oil ethoxylate available under the tradename Alkasurf CO-40 (fromRhone-Poulenc Mississauga Ontario,Canada); and mixtures thereof.

[0039] When mometasone is used, it is known that it has some solubilityin ethanol. As with other drugs which have solubility in ethanol, thereis a tendency for mometasone furoate to exhibit crystal growth inethanol-containing formulations. Formulation parameters which do notpromote drug particle size growth are known. These parameters providethe advantage of minimizing the required ethanol concentrations, toreduce the potential for unpleasant taste sensations and render thecompositions more suitable for use by children and others with lowalcohol tolerance.

[0040] A certain minimum level of ethanol is preferred to provideconsistent and predictable delivery of the drug from a metered dosedispenser. This minimum level is about 1 weight percent of the totalformulation, which results in a marginally acceptable drug delivery.Increased amounts of ethanol generally improve drug deliverycharacteristics. However, and to prevent drug crystal growth in theformulation, it is preferred to limit the concentration of ethanol.Experimental data indicate that the ratio of the weight of mometasonefuroate to the weight of ethanol is important in preventing particlesize increases.

[0041] Formulations of the invention are made according to procedurescustomary in the art for other aerosol compositions. Typically, allcomponents except the propellant are mixed and introduced into aerosolcontainers. The containers can then be chilled to temperatures below theboiling point of the propellant, and the required amount of the chilledpropellant added before the metering valve is crimped on to thecontainer. Alternatively, the containers can be fitted with a meteringvalve before being filled with propellant, and the required quantity ofpropellant will be introduced through the valve. The available meteringvalve delivery volumes range from about 25 to about 100 microliters peractuation, while the amounts of drug substance required in a dose fortreating a particular condition is generally about 10 to about 500micrograms per valve actuation. These two factors combined poselimitations that dictate the points within the foregoing ethanolparameters for a given formulation. The determination of such amounts iswithin the skill of workers in this art.

[0042] Depending on the particular application, the container may becharged with a predetermined quantity of formulation for single ormultiple dosing. Typically, the container is sized for multiple-dosing,and, therefore it is very important that the formulation delivered issubstantially uniform for each dosing. For example, where theformulation is for bronchodilation, the container typically is chargedwith a sufficient quantity of the formulation for 200 charges.

[0043] Suitable suspensions may be screened in part by observing severalphysical properties of the formulation, i.e. the rate of particleagglomeration, the size of the agglomerates and the rate of particulatecreaming/settling and comparing these to an acceptable standard. Such,suitable solutions may be screened/evaluated by measuring the solubilityof the medicament over the entire recommended storage temperature range.

[0044] Suspensions of the present invention preferably may be preparedby either the pressure filling or cold filling procedures known in theart.

[0045] For metered dose inhalers, suspensions may be particularlypreferred for efficacy and stability considerations.

[0046] Those skilled in the art may choose to add one or morepreservative, buffer, antioxidant, sweetener and/or flavors or othertaste masking agents depending upon the characteristics of theformulation.

[0047] The invention will be further described by means of the followingexamples, which are not intended to limit the invention, as defined bythe appended claims, in any manner.

EXAMPLE 1

[0048] Optical microscopy was performed using an Olympus BX60 modelpolarized light microscope; photomicrography was performed using adigital camera (DP 10-32); Image analysis of the generated image wasperformed using ImagePro Plus software on a Dell OptiPlex GX1 computerwith a Pentium III microprocessor; Two stage filling was performed byfilling with Pamasol.

[0049] The following ingredients and packages were utilized:

[0050] a) Teflon coated 14 mL cans from CCL (PFA);

[0051] b) Teflon coated 14 mL cans from Presspart (PFA optimized curingprocess);

[0052] c) Teflon coated 14 mL cans from CCL (FEP same as PFA without themelanine;

[0053] d) Epoxy coated 10 mL cans from Safet;

[0054] e) 25 μL valves from Valois;

[0055] f) 63 μL valves from Valois;

[0056] g) Mometasone furoate micronized drug substance;

[0057] h) Alcohol USP 200 proof;

[0058] i) Oleic acid NF (Emersol 6321);

[0059] j) HFC-227 propellant;

[0060] k) Pamasol Macromat Line 4400 from D. H. Industries Limited; and

[0061] l) Aluminum foil sheets

[0062] The following filling procedure was applied: Drug concentrate(Mometasone furoate micronized in alcohol USP 200 proof with oleic acidNF (Emersol 6321)) was prepared in three concentrations 1.81 mg/g, 0.96mg/g and 0.28 mg/g, and then metered into cans. The first twoconcentrations were metered into epoxy coated 10 mL cans while the thirdconcentrate was metered into 14 mL teflon FEP cans and 14 mL teflon PEFcans. The cans were crimped with the 25 μL valves (the first twoconcentrations) and the 63 μL (the third concentration). The HFC-227propellant was filled in to these cans up to 8 g total fill (the firsttwo concentrations) and up to a 15 g fill (the third concentration).

[0063] The cans were then cut open to analyze the effect of the drug onthe reflection from the can surfaces. The internal surface studied wasthe bottom flat part of the can. This approach was pursued to avoidspherical aberration interference. Spherical aberration is the mostserious imperfection that occurs during reflection off a surface wherebylight rays from a single point in the object are reflected from theouter zone of a spherical surface and are not focused at the same pointas the central rays.

[0064] The following procedure was used to obtain the digitalmicrographs:

[0065] Turn on the microscope. Insert the card into the camera and closethe card cover. The main switch on the camera must be in the offposition. Turn on the camera. Press the light intensity “Preset” buttonwhile making sure that the Transmitted/Reflected light selector switchis in the Reflected light position. Push the Aperture Iris (AS) and theField Iris (FS) Diaphragm knobs as well as the (SHUTTER) knob leavingthe diaphragms open. Adjust the Light Path Selector knob to the middleposition. Disengage the Analyzer and the Polarizer sliders from thelight path by sliding the filters out.

[0066] Next, remove the Differential Interference Contrast Prism fromthe light path by sliding the prism out until there is a click and theengraving can be seen. Tighten the clamping screw to secure the prism.Engage the LBD (color balance and filter) built-in filter by turning itslever so that the reference mark on the lever is aligned with thereference mark on the base.

[0067] Then, disengage the ND25 (natural density filter number 25) andND6 (natural density filter number 6) by turning their levers so thatthe reference marks are aligned with the reference marks on the base.Place the dummy plate on the stage and secure it with the specimenholders. Place the N 9.50 Munsell color standard (white surface up) onthe stage. Turn the nosepiece to engage the 5× objective.

[0068] Select picture quality by switching the manual switch box toSuper High Quality (SHQ) in the menu screen. Record mode should beactivated. Move the N 9.50 Munsell color standard with the white surfaceup to the center and directly under the light and press the AutoExposure Lock (AE LOCK) button to lock the exposure time and brightnessof the image center.

[0069] Place the standard sample on the stage and focus the image withthe coarse adjustment knob and then with the fine adjustment knob. Pressthe Exposure (EXPOSE) button to take a single picture. To preview thepicture, press the REC/PLAY button. Press REC/PLAY button to switch backto record mode. Repeat the steps in this paragraph for the rest of thesamples.

[0070] Thereafter, retrieve the picture from the database. Then, analyzethe image's brightness using the ImagePro Plus software.

[0071] The smoothness index is defined as follows: $\begin{matrix}{{{Smoothness}\quad {Index}} = {{Amount}\quad {of}\quad {Reflected}{\quad \quad}{Light}\quad {from}\quad {the}{\quad \quad}{Studied}{\quad \quad}{{Surface} \div}}} \\{{{Amount}{\quad \quad}{of}\quad {Light}\quad {Reflected}\quad {from}\quad {Aluminum}\quad {Foil}\quad {Standard}}}\end{matrix}$

[0072] The following samples were analyzed:

[0073] Each sample was photographed, the image was digitized and thedigital image was then analyzed using the ImagePro Plus software for theareas of brightness and darkness. The average measurement of the area ofbrightness is presented in pixels, i.e., for each sample the number of“bright” pixels were added. These were then divided by the number ofmeasurements and an average was obtained. The samples that showed thehigher numbers were brighter than the ones with lower numbers. Forinstance Teflon—Standard—FEP exhibited the highest average number of“bright area” pixels (181.9 pixels) and therefore had the smoothestsurface. The Teflon-PFA non-optimized was found to be least bright andhad the lowest average number of “bright area” pixels (111.7 pixels).The significance of this finding is that the technique is capable ofcharacterizing the quality of the studied can wall surface. In additionthe “Smoothness Index” is capable of quantifying the difference in thequality of the can wall surfaces. These data are shown in Table 1. TABLE1 Can Type Average Reflection (Pixels) Epoxy Can 132.8 Teflon PFA Can111.7 non-optimized Teflon PFA Can 171.5 optimized Teflon FEP Can 181.9Aluminum Foil 249.6

[0074] Each can type, Epoxy coated, Teflon-PFA and Teflon-FEP werephotographed, the image was digitized, and the digital images wereanalyzed for their bright area pixels as described in the previousparagraph (Table 2). The same types of cans were then analyzed in thepresence of known concentrations of drug. The pressurized cans werechilled, then cut open and the propellant was left to evaporate. Thenthe same section of the can (base) was analyzed for the average area ofbrightness. These areas in the presence of drug were invariably lessbright when compared to the same areas in the absence of drug.

[0075] The least bright were the Teflon-PFA coated cans in the presenceof drug which showed a 35% reduction in reflection when compared to thesame cans in the absence of drug. The Teflon-FEP coated cans in thepresence of drug showed an intermediate brightness and a 33% reductionin brightness when compared to the same cans in the absence of drug.Surprisingly the brightest were the Epoxy cans in the presence of drugand showed the least reduction in brightness (3%). These data arepresented in Table 2. TABLE 2 % Reduction Average Smooth- in ReflectionReflection Standard ness Due to Drug Can Type (Pixels) (Pixels) IndexAdhesion Epoxy Can 132.8 249.6 0.53 N/A (76588-054) Epoxy Can 128.7249.6 0.52  3% (with Drug 1.813 mg/g) Teflon PFA Can 171.5 249.6 0.69N/A optimized Teflon PFA Can 111.7 249.6 0.43 35% optimized (with Drug1.813 mg/g) Teflon FEP Can 181.9 249.6 0.73 N/A Teflon FEP Can 121.4249.6 0.54 33% (with Drug 1.813 mg/g) Aluminum Foil 249.6 249.6 1 N/A

[0076] Aluminum foil was used as a reference standard for a surface thatwould reflect most. And indeed its reflection (249.6 pixels) was veryclose to the digital camera's resolution limit of 250 pixels. Allconsequent measurements were compared to this standard using the“Smoothness Index” equation. Therefore, the closer the ratio to unitythe brighter was the studied sample/surface.

[0077] The foregoing descriptions of various embodiments of theinvention are representative of various aspects of the invention, andare not intended to be exhaustive or limiting to the precise formsdisclosed. Many modifications and variations undoubtedly will occur tothose having skill in the art. It is intended that the scope of theinvention shall be fully defined solely by the appended claims.

We claim:
 1. A method for determining a smoothness index of a metereddose container having an inner core comprising the steps of a)subjecting said inner core of said metered dose container to reflectedlight photomicrography to obtain a digital image containing a pluralityof pixels of said inner core; b) determining from said digital image thebrightness of each of said pixels and quantifying said brightness byassigning an integer value thereto, wherein said value corresponds to anamount of brightness; and c) comparing said brightness of said pixel toa reference standard to determine the smoothness index of said innercore of said metered dose container.
 2. A method for determining asmoothness index of a metered dose container having an inner corecomprising the steps of a) subjecting said inner core of said metereddose container containing at least one pharmacologically active agent toreflected light photomicrography to obtain a digital image containing aplurality of pixels of said inner core; b) determining from said digitalimage the brightness of each of said pixels and quantifying saidbrightness by assigning an integer value thereto, wherein said valuecorresponds to an amount of brightness; and c) comparing said brightnessof said pixel to a reference standard to determine the smoothness indexof said inner core of said metered dose container.
 3. The method fordetermining a smoothness index of a metered dose container having aninner core according to claim 2, wherein the at least onepharmacologically active agent is a corticosteroid.
 4. The method fordetermining a smoothness index of a metered dose container having aninner core according to claim 3, wherein the corticosteroid is selectedfrom the group consisting of mometasone furoate anhydrous;beclomethasone dipropionate; budesonide; fluticasone; dexamethasone;flunisolide; triamcinolone;(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione;and tipredane.
 5. The method for determining a smoothness index of ametered dose container having an inner core according to claim 4,wherein corticosteroid is mometasone furoate anhydrous.
 6. The methodfor determining a smoothness index of a metered dose container having aninner core according to claim 4, wherein the corticosteroid isbeclomethasone diproprionate.
 7. The method for determining a smoothnessindex of a metered dose container having an inner core according toclaim 4, wherein the corticosteroid is budesonide.
 8. The method fordetermining a smoothness index of a metered dose container having aninner core according to claim 4, wherein the corticosteroid isfluticasone.
 9. The method for determining a smoothness index of ametered dose container having an inner core according to claim 2,wherein the at least one pharmacologically active agent is a β-agonist.10. The method for determining a smoothness index of a metered dosecontainer having an inner core according to claim 9, wherein theβ-agonist is selected from the group consisting of albuterol,terbutaline, salmeterol, bitolterol, formoterol, eFormoterol,2(1H)-Quinolinone,8-hydroxy-5-[1-hydroxy-2-[[2-(4-(methoxyphenyl)-1-methylethyl]amino]ethyl]-monohydrochloride,[R—(R*,R*)]—.
 11. The method for determining a smoothness index of ametered dose container having an inner core according to claim 10,wherein β-agonist is albuterol.
 12. The method for determining asmoothness index of a metered dose container having an inner coreaccording to claim 10, wherein the β-agonist is terbutaline.
 13. Themethod for determining a smoothness index of a metered dose containerhaving an inner core according to claim 10, wherein β-agonist isformoterol.
 14. The method for determining a smoothness index of ametered dose container having an inner core according to claim 10,wherein the β-agonist is salmeterol.
 15. The method for determining asmoothness index of a metered dose container having an inner coreaccording to claim 2, wherein the at least one pharmacologically activeagent is selected from the group consisting of ipratropium bromide,oxitropium bromide, sodium cromoglycate, nedocromil sodium, montelukast,zafirlukast, pranlukast, bambuterol, fenoterol, clenbuterol, procateroland broxaterol.
 16. The method for determining a smoothness index of ametered dose container having an inner core according to claim 15,wherein the at least one pharmacologically active agent is montelukast.17. The method for determining a smoothness index of a metered dosecontainer having an inner core according to claim 2, wherein the atleast one pharmacologically active agent is selected from a combinationof a corticosteroid and a β-agonist.
 18. The method for determining asmoothness index of a metered dose container having an inner coreaccording to claim 17, wherein the corticosteroid is mometasone furoateanhydrous and the β-agonist is formoterol.
 19. The method fordetermining a smoothness index of a metered dose container according toclaim 17, wherein the corticosteroid is budesonide and the β-agonist isterbutaline.
 20. The method for determining a smoothness index of ametered dose container having an inner core according to claim 17,wherein the corticosteroid is fluticasone and the β-agonist issalmeterol.